Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability.
Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability.
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在羧酰胺三唑诱导的营养不可用的压力下，靶向谷氨酰胺的利用来阻止肿瘤细胞的代谢适应
DOI：
10.1016/j.apsb.2021.07.008
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Shi J;Ju R;Gao H;Huang Y;Guo L;Zhang D
肿瘤细胞具有独特的代谢程序，在生物学上与相应的正常细胞不同。重置肿瘤代谢规划是改善肿瘤耐药和改善肿瘤微环境的一种很有前途的策略。在这里，我们证明了抗癌药物羧胺三唑(CaI)可以作为代谢调节剂，降低糖和脂代谢，增加结肠癌细胞对谷氨酰胺代谢的依赖。CaI抑制糖脂代谢利用，抑制线粒体呼吸链复合体I，从而产生活性氧(ROS)。同时，芳香烃受体(AhR)的激活通过转运体SLC1A5增加了谷氨酰胺的摄取，从而激活了ROS清除酶谷胱甘肽过氧化物酶。因此，联合应用GLS/GDH1、CA1抑制剂可有效抑制结直肠癌的能量代谢。这些数据阐明了一种新的抗肿瘤机制，为结直肠癌的代谢重编程治疗提供了一种新的策略。细胞抑制剂CA1抑制葡萄糖和脂肪代谢的利用，进一步增加肿瘤细胞对谷氨酰胺代谢的依赖，提示与谷氨酰胺代谢途径抑制剂的协同抗癌策略。
Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment. The cytostatic agent CAI suppresses glucose and lipid metabolism utilization and further increases tumour cell dependency on glutamine metabolism, suggesting a synergistic anticancer strategy with glutamine metabolic pathway inhibitors.
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影响因子：
4.1
作者：
KOVACEVIC, Z
通讯作者：
KOVACEVIC, Z
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
21.3
作者：
Boroughs LK;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
20.3
作者：
Jacque, Nathalie;Ronchetti, Anne Marie;Bouscary, Didier
通讯作者：
Bouscary, Didier
羧酰胺三唑与索拉非尼协同通过抑制 NANOG 和加剧细胞凋亡来对抗非小细胞肺癌
DOI：
10.1124/jpet.117.240986
发表时间：
2017-08-01
影响因子：
3.5
作者：
Chen, Chen;Ju, Rui;Guo, Lei
通讯作者：
Guo, Lei